The present invention relates to processes for the production of piperidine derivatives.
Terfenadine, 1-(p-tert-butylphenyl)-4- [4xe2x80x2-(xcex1-hydroxydiphenylmethyl)-1xe2x80x2-piperidinyl]-butanol is a non-sedating anti-histarnine. It is reported to be a specific H1-receptor antagonist that is also devoid of any anticholingeric, anti-serotoninergic, and anti-adrenergic effects both in vitro and in vivo. See D. McTavish, K. L. Goa, M. Ferrill, Drugs, 1990, 39, 552; C. R. Kingsolving, N. L. Monroe, A. A. Carr, Pharmacologist, 1973, 15, 221; J. K. Woodward, N. L. Munro, Arzneim-Forsch, 1982, 32, 1154; K. V. Mann, K. J. Tietze, Clin. Pharm. 1989, 6, 331. A great deal of effort has been made investigating structure-activity relationships of terfenadine analogs, and this is reflected in the large number of U.S. patents disclosing this compound and related structures as follows:
U.S. Pat. No. 3,687,956 to Zivkovic
U.S. Pat. No. 3,806,526 to Carr, et. al.
U.S. Pat. No. 3,829,433 to Carr, et. al.
U.S. Pat. No. 3,862,173 to Carr, et. al.
U.S. Pat. No. 3,878,217 to Carr, et. al.
U.S. Pat. No. 3,922,276 to Duncan, et. al.
U.S. Pat. No. 3,931,197 to Carr, et. al.
U.S. Pat. No. 3,941,795 to Carr, et. al.
U.S. Pat. No. 3,946,022 to Carr, et. al.
U.S. Pat. No. 3,956,296 to Duncan, et. al.
U.S. Pat. No. 3,965,257 to Carr, ct. al.
U.S. Pat. No. 4.742,175 to Fawcett, et. al.
In animal and human metabolic studies, terfenadine has been shown to undergo extensive hepatic first-pass metabolism, and after usual dosages it cannot be detected in plasma unless very sensitive assayls are used. A specific hepatic cytoclrome P-450 enzyme converts terfenadine to the major metabolite 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydrox),butyl]-xcex1-xcex1-dimethylphenylacetic acid, also known as terfenadine carboxylic acid metabolite. This metabolite can be readily detected in plasma and is considered to be the active form of orally administered terfenadine.
Side effects reported ws ith terfenadine are cardiac arrhythmias (ventricular tachyarrhythmias, torsades de points, ventricular fibrillation), sedation, GI distress, dry mouth, constipation and/or diarrhea. The most serious of these, and potentially life threatening, are cardiac arrhythlmias, which are related to terfenadine""s ability to prolong the cardiac QT interval, and are only reported in patients administered terfenadine with liver disease or who also take the antifungal drug ketoconazole or the antibiotic erythromycin. As a result of these adverse events, the FDA, in 1992, required terfenadine to include a warning label. Although OTC formulations of terfenadine are purportedly being developed, the potentially serious side effects seen in some patients will be a significant obstacle for regulatory approval.
Since cardiac side effects of terfenadine have been reported in patients with impaired liver function, as well as in patients also taking antibiotics known to suppress hepatic enzyme function, it was speculated that the cardiac side effects were due to accumulation of terfenadine and not due to accumulation of terfenadine carboxylic acid metabolite. Patch clamp studies in isolated feline ventricular myocytes support the contention that terfenadine, and not the carboxylic acid metabolite, is responsible for cardiac side effects. At a concentration of 1 xcexcM, terfenadine caused a greater than 90% inhibition of the delayed rectifier potassium current. At concentrations up to 5 xcexcM, the terfenadine carboxylic acid metabolite had no significant effect on the potassium current in this assay (See R. L. Woosley, Y. Chen, J. P. Frieman, and R. A. Gillis, JAMA 1993, 269, 1532). Since inhibition of ion transport has been linked to cardiac abnormalities such as arrhythmias, these results indicate that terfenadine carboxylic acid is likely not liable to cause cardiac arrhythmias, at dose levels at which there is a distinct risk of such a side effect being caused by terfenadine itself.
Carebastine, 4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-oxobutyl]-xcex1,xcex1-dimethylphenylacetic acid, is the carboxylic acid metabolite of ebastine, 1-(p-tert-butylphenyl)-4-[4xe2x80x2-(xcex1-diphenylmethoxy)-1xe2x80x2-piperidinyl]-butanol. Both compounds possess potent selective histamine H1-receptor blocking and calcium antagonist properties and should prove useful in the treatment of a variety of respiratory, allergic, and cardiovascular disease states.
These compounds relax bronchial and vascular smooth muscle in vitro and in vivo and inhibit the constrictor influence of noradrenaline, potassium ions, and various other agonist drugs. The compounds also inhibit responses of intestinal and tracheal preparations to histamine, acetylcholine, and barium chloride and block the bronchoconstriction induced by histamine aerosol in guinea pigs in doses less than 1 mg/kg animal body weight administered orally. They also possess antianaphylactin properties in the rat, inhibit the skin lesions to a variety of anaphylactic mediators (histamine, 5-hydroxytryptamine, bradykinin, LCD4, etc.), and antagonize the Schultz-Dalc response in the sensitive guinea-pig.
Piperidine derivatives related to the terfenadine carboxylic acid metabolite are disclosed in the following U.S. patents:
U.S. Pat. No. 4,254,129 to Carr, et. al.
U.S. Pat. No. 4,254,130 to Carr, et. al.
U.S. Pat. No. 4,285,957 to Carr, et. al.
U.S. Pat. No. 4,285,958 to Carr, et. al.
In these patents, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetic acid and related compounds are prepared by alkylation of a substituted piperidine derivative of the formula: 
with an xcfx89-haloalkyl substituted phenyl ketone of the formula: 
wherein the substituents halo, R1, R2, n, Z, and R6 are described in column 6 of U.S. Pat. No. 4,254,130.
In similar fashion, U.S. Pat. No. 4,550,116 to Soto et al. describes preparation of piperidine derivatives related to carebastine by reacting the xcfx89-haloalkyl substituted phenyl ketone with a substituted hydroxypiperidine derivative of the formula: 
U.S. Pat. No. 4,254,130 indicates that xcfx89-haloalkyl substituted phenyl ketones, wherein Z is hydrogen, are prepared by reacting an appropriate straight or branched lower alkyl C1-6 ester of xcex1-xcex1-dimethylphenylacetic acid with a compound of the following formula: 
under the general conditions of a Friedel-Crafts acylation, wherein halo and m are described in columnn 11 of U.S. Pat. No. 4,254,129. The reaction is carried out in carbon disulfide as the preferred solvent.
Other procedures for producing terfenadine carboxylic acid metabolite are disclosed in PCT Application Nos. WO95/00482, WO94/03170, and WO95/00480.
The present invention is directed toward an improved process for preparation of terfenadine carboxylic acid metabolite and carebastine.
Thie present invention relates to processes for preparing piperidine derivative compounds of the formulae: 
wherein
n is 0 or 1;
R1 is hydrogen or hydroxy;
R2 is hydrogen;
or, when n is 0, R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2, provided that when n is 1, R1 and R2 are each hydrogen;
R3 is xe2x80x94COOH or xe2x80x94COOR4;
R4 is an alkyl or aryl moiety;
A, B, and D are the substituents of their rings, each of which may be different or the same, and arc selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents or a salt thereof The piperidine derivative compound is prepared by providing a regioisomer having the following formula: 
wherein
Z is xe2x80x94CG1G2G3, 
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S, and NR5;
G1, G2, and G3 are the same or different and are selected from the group consisting of OR8, SR8, and NR8R9;
R6 and R7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR8, SR8, and NR8R9; and
R5, R8, and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety.
The regioisomer is then converted to the piperidine derivative having a keto group with a piperidine compound.
The invention further relates to a regioisomer having the formula: 
The present invention is also directed to processes for preparing a regioisomer having the formula: 
In one aspect of the invention, the process for preparing the regioisomer includes acylating an xcex1,xcex1-disubstituted-methylbenzene derivative having the formula: 
wherein
X1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, alkylhalo silicon. trialkyl silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions
with a compound having the formula: 
wherein
X2 is a halogen; an alkali metal oxide; a moiety having the formula xe2x80x94OR10; a moiety having the formula xe2x80x94SR10; or an amine; and
R10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety
under conditions effective to produce the regioisomer.
In another aspect of the present invention, the process for preparing the regioisomer includes reacting a 4-(xcex1,xcex1-disubstituted)-toluic acid derivative having the formula: 
wherein
X2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula xe2x80x94OR10: a moiety having the formula xe2x80x94SR10; or an amine; and
R10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety
with a compound having the formula: 
wherein
X1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, alkylhalo silicon, trialkyl silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions
under conditions effective to produce the regioisomer.
In yet another aspect of the invention, the process of preparing a regioisomer includes providing an xcex1,xcex1-diunsubstituted regioisomer precursor having the formula: 
and methylating the xcex1,xcex1-diunsubstituted regioisomer precursor under conditions effective to produce the regioisomer.
The present invention is also directed to an xcex1,xcex1-disubstituted-methylbenzene derivative having the formula: 
and to an xcex1,xcex1-diunsubstituted-methylbenzene derivative having the formula: 
The invention further relates to an oxobutyl derivative having the formula: 
as well as to piperidine derivative precursors having the formulae: 
The present invention relates to a process for preparing piperidine derivative compounds having the formulae: 
wherein
n is 0 or 1;
R1 is hydrogen or hydroxy;
R2 is hydrogen; or, when n is 0, R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2, provided that when n is 1, R1 and R2 are each hydrogen;
R3 is xe2x80x94COOH or xe2x80x94COOR4;
R4 is an alkyl or aryl moiety;
A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents
or a salt thereof.
These piperidine derivative compounds may be in the form of 4-diphenylmethylpiperidine derivatives represented by the following formulae: 
where A, B, D, and R3 are defined above. The piperidine derivative compounds also include 4-(hydroxydiphenylmethyl)piperidine derivatives according to the following formulae: 
where A, B, D, and R3 are defined above. Another useful class of piperidine derivative compounds are 4-diphenylmethylenepiperidine derivatives in accordance with the following formulae: 
where A, B, D, and R3 are defined above.
Another useful class of piperidine derivative compounds are 4-diphenylmethoxypiperidine derivatives having the following fonnulac: 
where A, B, D, and R3 are defined above.
Examples of R4 are substituted or unsubstituted, straight or branched alkyl groups, including methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, benzyl, and 4-methylbenzyl groups and substituted or unsubstituted aryl groups, including phenyl, tolyl, and xylyl groups.
Illustrative examples of compounds prepared by the process of the present invention are as follows:
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetic acid;
4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetic acid;
4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetic acid;
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-3-hydroxybenzeneacetic acid;
4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-2-hydroxybenzeneacetic acid;
4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-3-hydroxybenzeneacetic acid;
4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetic acid;
ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetate;
n-pentyl 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetate;
ethyl 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetate;
methyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetate;
ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-(3-hydroxybernzene)acetate;
n-propyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-(2-hydroxybenzene)acetate;
n-hexyl 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-(3-hydroxybenzene)acetate;
ethyl 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetate;
4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetic acid;
4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-3-hydroxybenzeneacetic acid;
4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-2-hydroxybenzeneacetic acid;
4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-3-hydroxybenzeneacetic acid;
4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetic acid;
n-pentyl 4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetate;
ethyl 4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetate;
ethyl 4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-(3-hydroxybenzene)acetate;
n-propyl 4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-(2-hydroxybenzene)acetate;
n-hexyl 4-[4-[4-(diphenylmethoxy)-1-piperidiiyl]-1-hydroxybutyl]-xcex1,xcex1-dimethyl-(3-hydroxybenzene)acetate; and
ethyl 4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-hydroxybutyl]-xcex1,xcex1-dimethylbenzeneacetate.
Particularly preferred are compounds of the formulae: 
Optionally, both phenyl groups from the piperidine compound may be alkyl (e.g., methyl, substituted at the position para to the methylene, such as 
The compounds prepared by the methods of the present invention can be pharmaceutically acceptable salts in the form of inorganic or organic acid or base addition salts of the above compounds. Suitable inorganic acids arc, for example, hydrochloric. hydrobromic, sulfuric, and phosphoric acids. Suitable orcanic acids include carboxylic acids, such as, acetic, propionic, glycolic, lactic, pyruvic. malonic, succinic, fumanec, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, anthranilic, cianamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid. Sulfonic acids, such as, methanesulfonic, ethanesulfonic, and xcex2-hydroxyethane-sulfonic acid are also suitable acids. Non-toxic salts of the compounds of the above-identified formulae formed with inorganic and organic bases include, for example, those alkali metals, such as, sodium, potassium, and lithium, alkaline earth metals, for example, calcium and magnesium, light metals of group IIIA, for example, aluminum, organic amines, such as, primary, secondary, or tertiary amines, for example, cyclohexylamine, ethylamine, pyridine, methylaminoethanol, and piperazine. These salts are prepared by conventional means, for example, by treating the piperidime derivative compounds of the formulae: 
where A, B, D, n, R1, R2, and R3 are defined above, with an appropriate acid or base.
The piperidine derivative compounds prepared by the methods of the present invention can be utilized as the biologically active components in pharmaceutical compositions. These compounds are useful as antihistamines, antiallergy agents, and bronchodilators. They may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.
The compounds prepared by the methods of this invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes. Such application to mucous membranes can be achieved with an aerosol spray containing small particles of a compound of this invention in a spray or dry powder form.
The quantity of the compound administered will vary depending on the patient and the mode of administration and can be any effective amount. The quantity of the compound administered may vary over a Aide range to provide in a unit dosage an effective amount of from about 0.01 to 20 mg/kg of body weight of the patient per day to achieve the desired effect. For example, the desired antihistamine, antiallergy, and bronchodilator effects can be obtained by consumption of a unit dosage form such as a tablet containing 1 to 50 mg of the compound of the present invention taken 1 to 4 times daily.
The solid unit dosage forms can be of the conventional type. This solid form can be a capsule, such as an ordinary gelatin type containing the compound of the present invention and a carrier, for example, lubricants and inert fillers such as, lactose, sucrose, or cornstarch. In another embodiment, these compounds are tableted with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents such as, cornstarch, potato starch, or alginic acid, and a lubricant like stearic acid or magnesium stearate.
The compounds prepared according to this invention may also be administered in injectable dosages by solution or suspension of the compounds of the present invention in a physiologically acceptable diluent with a pharmaceutical carrier. Such carriers include sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.
For use as aerosols, the compounds in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane. or isobutane with conventional adjuvants. These compounds may be administered in a non-pressurized foirn, such as in a nebulizer or atomizer.
The compounds made according to the present invention can be used to treat warm blooded animals, birds, and mammals. Examples of such beings include humans, cats, dogs, horses, sheep, cows, pigs, lambs, rats, mice, and guinea pigs.
According to one aspect of the present invention, the piperidine derivative compounds are prepared by providing a regioisomer of the following formula: 
and converting the regioisomer to the piperidine derivative compounds of the invention having a keto group with a piperidine compound.
The resulting piperidine derivative compounds with a keto group can then be converted by reduction to the above-described piperidine compounds with a hydroxyl group.
A is the substituents of its ring, each of which may be different or the same and is selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substituents.
Z can be a carbon atom to which are bonded three electron rich groups, such as moieties having the formula CG1G2G3. G1, G2, and G3 can be the same or different and are illustratively selected from the group consisting of OR8, SR8, and NR8R9, where R8 and R9 arc the same or different and can be hydrogen; an alky,l moiety, including substituted or unsubstituted, branched or straight-clhain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, benzyl, and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; or an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, and xylyl. Examples of such a Z include triethoxymethyl or trimethoxymethyl moieties.
Z can also be a heterocyclic moiety having the formulae: 
where m is an integer from 1 to 6 and Q and Y are independently oxygen, sulfur, or a substituted or unsubstituted amine having the formula NR5. R5 can be hydrogen; an alkyl moiety, including substituted or unsubstituted, branched or straight-chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, benzyl, and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; or an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, and xylyl groups. It is to be understood that R6 and R7, the two substituents bonded to each methylene (i.e. CH2 group), of which there are m in the above formulae, are independently selected from each other. In addition, it is to be understood that R6 groups and R7 groups on one methylene can be the same or different than those on other methylenes. Each R6 and each R7 can be hydrogen; an alkyl moiety, including substituted or unsubstituted, branched or straight-chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, 2-methylpentyl, cyclohexyl, benzyl, and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, xylyl, and naphthyl; or a moiety having the formulae OR8, SR8, or NR8R9, where R8 and R9 are defined as they were above where Z had the formula CG1G2G3. Preferred examples of Z include isoxazoline moieties having the formula: 
wherein R6, R7, R12, and R13 are the same or different and can be hydrogen; an alkyl moiety, including substituted or unsubstituted, branched or straight-chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, 2-methylpentyl, cyclohexyl, benzyl, and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, xylyl, and naphthyl; or a moiety having the formulae OR8, SR8, or NR8R9, where R8 and R9 are as defined as they were above. Preferably, m is 2, and R12 and R13 are hydrogen. More preferably, R12 and R13 are hydrogen, and R6 and R7 are each an alkyl moiety having from 1 to 7 carbon atoms. Most preferably, Z is 4,4-dimethylisoxazolin-2-yl, where each of R12 and R13 is hydrogen and R6 and R7 is methyl.
A variety of methods can be used to provide these regioisomers.
In one embodiment of the present invention, the regioisomer is produced by acylating an xcex1,xcex1-disubstituted-methylbenzene derivative having the formula: 
with a compound having the formula: 
under conditions effective to produce the regioisomer having the formula: 
In this embodiment, the acylation agent is a cyclopropyl derivative.
In another embodiment of the present invention, the acylation agent is a 4-(xcex1,xcex1-disubstituted)-toluic acid derivative. In this embodiment, the regioisomer is produced by reacting a 4-(xcex1,xcex1-disubstituted)-toluic acid derivative having the formula: 
with a compound having the formula: 
under conditions effective to acylate the compound, producing the regloisomer.
Irrespective of whether the regioisomer is produced using the process employing a cyclopropyl derivative acylation agent or the process employing a 4-((xcex1,xcex1-disubstituted)-toluic acid derivative acylation agent, X1 can be a halogen; trialkyl or triaryl tin; trialkyl or triaryl borate; alkylhalo silicon; trialkyl silicon; or a substituted sulfonic ester, such as tosylate, mesylate, or triflate, with any alkyl groups being straight or branched and preferably having 1 to 4 carbon atoms. Alternatively, X1 can be a substituent usefull in organometallic coupling reactions, including lithium or magnesium compounds derived from bromine or iodine. As used herein, alkylhalo silicon is a tetravalent silicon atom bonded to at least one halogen and at least one alkyl group. The remaining silicon valency is bonded to either a second halogen or a second alkyl. One particularly useful alkylhalo silicon has the formula xe2x80x94SiCH3F2.
X2, in either embodiment, can be hydrogen; a halogen; an alkali metal oxide; a moiety having the formula xe2x80x94OR10; a moiety having the formula xe2x80x94SR10; or an amine. Suitable amines are those having the formula xe2x80x94NR10R11 or xe2x80x94NR10(OR11); saturated cyclic amines, such as those having the formnulae: 
or heteroaryl amines, such as imidazole, pyrazole, and the like. R10 and R11 are the same or different and are selected from the group consisting of hydrogen; an alkyl moiety, including substituted or unsubstituted, branched or straight-chain alkyl moieties, such as methyl, ethyl, n-propy,l, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, benzyl, and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; and an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, and xylyl groups; p is an integer, preferably from 2 to 8.
In practicing the process employing a cyclopropyl derivative acylation agent, suitable acylation agents include cyclopropylcarboxylic acid halides, alkali metal cyclopropylcarboxylic acid salts, cyclopropylcarboxylic acid esters, or cyclopropylcarboxylic acid amides.
Suitable cyclopropylcarboxylic acid halides include cyclopropylcarboxylic acid fluoride, cyclopropylcarboxylic acid chloride, and cyclopropylcarboxylic acid bromide. Where an alkali metal salt of cyclopropylcarboxylic acid is employed as the acylation agent, suitable alkali metals include lithium, sodium, and potassium.
Cyclopropylcarboxylic acid amides can be N-unsubstituted amides, such as cyclopropylcarboxylic acid amide; an N-monosubstituted amide, such as N-methyl cyclopropylcarboxylic acid amide, N-ethyl cyclopropylcarboxylic acid amide, N-propyl cyclopropylcarboxylic acid amide, and N-hexyl cyclopropylcarboxylic acid amide; or an N,N-disubstituted amide. Suitable N,N-disubstituted amides include N,N-dimethyl cyclopropylcarboxylic acid amide, N-methyl-N-ethyl cyclopropylcarboxylic acid amide, N-methyl-N-propyl cyclopropylcarboxylic acid amide, N-methyl-N-hexyl cyclopropylcarboxylic acid amide, N,N-diethyl cyclopropylcarboxylic acid amide, N-ethyl-N-propyl cyclopropylcarboxylic acid amide, N-ethyl-N-hexyl cyclopropylcarboxylic acid amide, N,N-dipropyl cyclopropylcarboxylic acid amide, N-propyl-N-hexyl cyclopropylcarboxylic acid amide, and N,N-dihexyl cyclopropylcarboxylic acid amide. N,N-disubstituted cyclopropylcarboxylic acid amides having the formula xe2x80x94NR10(OR11), such as N-methyl-N-methoxy cyclopropylcarboxylic acid amide, N-methyl-N-ethoxy cyclopropylcarboxylic acid amide, N-ethyl-N-methoxy cyclopropylcarboxylic acid amide, and N-ethyl-N-ethoxy cyclopropylcarboxylic acid amide, are particularly useful. Suitable N,N-disubstituted amides also include cyclic amides, such as cyclopropyl carboxylic acid morpholine amide, cyclopropyl carboxylic acid piperazine amide, cyclopropyl carboxylic acid imidazole amide, and cyclopropyl carboxylic acid pyrazole amide, as well as those having the formula: 
where p is an integer, preferably from 2 to 8, examples of which include N,N-ethylene cyclopropylcarboxylic acid amide, N,N-propylene cyclopropylcarboxylic acid amide, N,N-butylene cyclopropylcarboxylic acid amide, and N,N-pentylene cyclopropylcarboxylic acid amide.
Irrespective of whether the regioisomer is produced using the process employing a cyclopropyl derivative acylation agent or the process employing a 4-(xcex1,xcex1-disubstituted)-toluic acid derivative acylation agent, the acylation reactions are carried out in a suitable solvent in the presence of an appropriate catalyst for about I to 120 hours and at temperatures of about xe2x88x9278xc2x0 C. to the reflux temperature of the solvent. Suitable solvents for acylation include: hydrocarbon solvents, such as benzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons, such as chlorobenzene, dichloroethane, methylene chloride, chloroform, or carbon tetrachloride; carbon disulfide; dimethylformamide; ethereal solvents, like tetrahydrofuran and diethylether; or dioxane.
In practicing either of the above processes, a variety of catalysts may be utilized when A is hydrogen. Suitable catalysts include palladium catalysts, like palladium chloride, palladium acetate, tetrakis(triphenylphosphine) palladium(0), dichlorobis(triphenylphosphine) palladium(II), or benzylchlorobis(triphenylphosphine)palladium(II); or nickel-phosphine catalysts. Acylation may also be carried out in the presence of added lithium chloride or triphenylphosphine. The latter acylation reaction is known in the art as organometallic cross-coupling reactions and are conducted by the general procedures of D. Milstein, et al., J. Org. Chem., 1979, 44, 1613; J. W. Labadie, et al., J. Org. Chem., 1983, 48, 4634. C. Salilberg, et al., Tetrahedron Letters, 1983, 24, 5137; D. Milstein, et al., J.Am. Chem. Soc., 1978, 100, 3636; and K. Tamao, et al., Tetrahedron, 1982, 38, 3347, all of which are hereby incorporated by reference.
Where acylation is ca ied out using the process employing a cyclopropyl derivative acylation agent, the reaction can also be promoted by addition of an acylation promoter which, when reacted with the mcthylbenzene derivative, displaces X1 from the benzene ring, forming a reactive carbanion salt. One suitable acylation promoter is butyl lithium, which is particularly effective when X2 is an amine. When X2 is chloride, preferred acylation promoters are magnesium metal or tetraalkyl tin. Acylation promoters, especially organometallics such as butyl lithium, are highly reactive with carbonyl groups. For this reason, the Z moiety is chosen to minimize reactivity of the carbon beta to the benzene ring. In particular, when employing an acylation promoter, Z moieties having the formula: 
such as isoxazolidium groups, are preferred.
The xcex1,xcex1-disubstituted-methylbenzene derivative having the formula: 
can be provided by reacting an xcex1,xcex1-diunsubstituted-methylbenzene derivative having the formula: 
with a methylating agent under conditions effective to produce the xcex1,xcex1-disubstituted-methylbenzene derivative. The methylation reaction is carried out in a suitable solvent and in the presence of a suitable non-nucleophilic base, such as potassium t-butoxide, sodium hydride, lithium diisopropylamide (xe2x80x9cLDAxe2x80x9d), lithium hexamethyldisilazide (xe2x80x9cLHMDSxe2x80x9d), potassium hexamethyldidisilazide (xe2x80x9cKHMDSxe2x80x9d), sodium or lithium tetramethylpiperidine, or related strong bases, for about 1 to about 120 hours, at temperatures from about xe2x88x9278xc2x0 C. to room temprature. Preferably, the reaction is conducted under an inert, dry atmosphere, such as N2 or Ar gas, in an inert, dry solvent. Suitable solvents for methylation include: hydrocarbon solvents, such as benzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons, such as chlorobenzene, dichloroethane, methylene chloride, or carbon tetrachloride; carbon disulfide; dimethylformamide; ethereal solvents, like tetrahydrofuran, t-butyl methyl ether, and diethylether; or dioxane. At least two molar equivalents and, preferably, between 2.1 and 3 molar equivalents of methylating agent are employed and added over the course of the reaction, either continuously or in two or more slugs. Suitable methylating agents include iodomethane, bromomethane, chloromethane, dimethyl sulfate, and the like.
The xcex1,xcex1-diunsubstituted-methylbenzene derivatives having the formula: 
can be prepared by reacting the correponding xcex1,xcex1-diunsubstituted benzylic acid of the formula: 
with an appropriate aminoalkyl derivative having the formula:
H2Nxe2x80x94(CR6R7)mxe2x80x94Qxe2x80x94H
under conditions effective to produce the xcex1,xcex1-diunsubstituted-methylbenzene derivative. This reaction is conducted in a suitable solvent for about 1 to about 120 hours and at a temperature ranging from 0xc2x0 C. to the reflux temperature of the solvent. Suitable solvents for this reaction include: hydrocarbon solvents, such as benzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons, such as chiorobenzene, dichlorethane, methylene chloride, chloroform, or carbon tetrachloride; carbon disulfide; dimethylformamide; etheral solvents, like tetrahydrofuran and diethylether; or dioxane. Preferably, the solvent is maintained at reflux in an apparatus having a means for removing water, such as a Dean-Stark trap. In many cases, it is advantageous to convert the (xcex1,xcex1-diunsubstituted-benzylic acid derivative to the corresponding acid halide, such as by treatment with thionyl chloride, prior to reaction with the aminoalkyl derivative.
Alternatively, the xcex1,xcex1-disubstituted-methylbenzene derivative having the formula: 
can be prepared from the corresponding xcex1,xcex1-disubstituted-benzylic acid derivative having the formula: 
by reacting the xcex1,xcex1-disubstituted-benzylic acid derivative with the above aminoalkyl derivative under the conditions described above with respect to the xcex1,xcex1-diunsubstituted-benzylic acid conversion.
The xcex1,xcex1-disubstituted-benzylic acid derivative used to prepare the xcex1,xcex1-disubstituted-methylbenzene derivative can be synthesized by methylating the corresponding xcex1,xcex1-diunsubstituted-benzylic acid derivative. Conditions suitable to carry out this methylation are the same as those described above with respect to methylation of xcex1,xcex1-diunsubstituted-methylbenzene derivatives.
Where acylation is carried out with a 4-(xcex1,xcex1-disubstituted)-toluic acid derivative having the formnula: 
the 4-(xcex1,xcex1-disubstituted)-toluic acid derivative can be provided by reacting a 4-(xcex1,xcex1-diunsubstituted)-toluic acid derivative having the formula: 
with a methylating agent under conditions effective to produce the 4-(xcex1,xcex1-disubstituted)-toluic acid derivative. Suitable methylation conditions are the same as those described above. The 4-(xcex1,xcex1-diunsubstituted)-toluic acid derivatives having the formula: 
can be prepared by reacting the correponding 4-(xcex1-carboxy-xcex1,xcex1-diunsubstituted)-toluic acid derivative having the formula: 
with an appropriate aminoalkyl derivative having the formula:
H2Nxe2x80x94(CR6R7)mxe2x80x94Qxe2x80x94H
under conditions effective to produce the 4-(xcex1,xcex1-diunsubstituted)-toluic acid derivative. Conditions suitable to effect this reaction are the same as those given above for reaction of xcex1,xcex1-diunsubstituted-methylbenzene derivatives with aminoalkyl derivatives.
Alternatively, the 4-(xcex1,xcex1-disubstituted)-toluic acid derivative having the formula: 
can be prepared from the corresponding 4-(xcex1-carboxy-xcex1,xcex1-disubstituted)-toluic acid derivative having the formula: 
by reacting the 4-(xcex1-carboxy-xcex1,xcex1-disubstituted)-toluic acid derivative with the above aminoalkyl derivative under the conditions described above with respect to the reaction of xcex1,xcex1-diunsubstituted-benzylic acid derivatives with aminoalkyl derivatives.
The 4-(xcex1-carboxy-xcex1,xcex1-disubstituted)-toluic acid derivative used to prepare the 4-(xcex1,xcex1-disubstituted)-toluic acid derivative can be synthesized by methylating the corresponding 4-(xcex1-carboxy-xcex1,xcex1-diunsubstituted)-toluic acid derivative. Conditions suitable for carrying out this methylation are the same as those described above with respect to methylation of xcex1,xcex1-diunsubstituted-methylbenzene derivatives.
The regioisomer of the present invention having the formula: 
can also be prepared from a corresponding (xcex1,xcex1-diunsubstituted regioisomer precursor having the formula: 
by methylation using reagents and conditions described above with respect to the methylation of xcex1,xcex1-diunsubstituted-methylbenzene derivatives. When employing this route, the (xcex1,xcex1-diunsubstituted regioisomer precursor is conveniently prepared from a (xcex1,xcex1-diunsubstituted-methylbenzene derivative having the formnula: 
by acylating the xcex1,xcex1-diunsubstituted-methylbenzene derivative with an acylation agent having the formula: 
under conditions effective to produce the xcex1,xcex1-diunsubstituted regioisomer precursor. Acylation conditions suitable for this reaction are the same as those described above with respect to acylation of xcex1,xcex1-disubstituted-methylbenzene derivatives.
Once the regioisomer is provided, it is then converted to the piperidine derivative with a piperidine compound.
In one aspect of the invention, the regioisomer having the formula: 
is reacted with a piperidine compound having the formula: 
R17 and R18 in the above formnula can be the same or different and are selected from the group consisting of an alkyl moiety, including substituted or unsubstituted, branched or straight-chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, benzyl, and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; and an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, and xylyl groups. Preferably, the reaction is conducted under an inert, dry atmosphere, such as nitrogen or argon, in an inert, dry solvent, at temperatures from about xe2x88x9250 xc2x0 C. to about the reflux temperature of the solvent. Suitable solvents include hydrocarbon solvents, such as benzene, toluene, xylene, or cyclolhexane; dimethylformarnmide; ethereal solvents, like tetrahydrofuran, t-butyl methyl ether, and diethylether; or dioxane.
In another aspect of the present invention, conversion of the regioisomer to the piperidine derivative is effected by halogenating, hydroxylating, alkoxylating, or aryloxylating the regioisomer under conditions effective to form a first intermediate compound having the formula: 
wherein X3 is a halogen or a hydroxy, alkoxy, or aryloxy moiety.
Suitable halogens include chlorine, bromine, and iodine. Suitable conditions for carrying out halogenating include reacting the regioisomer with a halogen nucleophile and a Lewis Acid. The halogenation reaction is carried out in a suitable solvent, optionally in the presence of a catalytic amount of base, for about 0.5 to 24 hours and a temperature of about xe2x88x9240 degrees C. to the reflux temperature of the solvent. Suitable halogen nucleophiles include sodium iodide, sodium bromide, potassium iodide, potassium bromide, cesium iodide. cesium bromide, trimethylsilyl iodide, manganese iodide, cerium iodide, magnesium bromide, magnesium iodide, magnesium carbonate, calcium bromide, and calcium iodide. Suitable Lewis Acids include silicon compounds, such as trimethylsilyl chloride and trimethylsilyl iodide; aluminum compounds, such as aluminum chloride, trimethyl aluminum, diethyl aluminum chloride, ethyl aluminum dichloride, and diethyl aluminum cyanide; magnesium salts; and boron salts. Suitable solvents for the halogenation reaction include alcohols, such as methanol, ethanol, isopropanol, and various glycols; hydrocarbon solvents, such as, benzene, toluene, xylene, or cyclohexane; ethereal solvents such as ether, tetrahydrofuran, dioxane, or dimethoxyethane; or halogenated hydrocarbons, such as, chlorobenzene, methylene chloride, carbon tetrachloride, chloroform, or dichloroethane.
The halogenation reaction can be conducted in a mixture of organic solvent and mineral acid, such as hydrochloric acid, hydrobromic acid, or hydroiodic acid. In this manner, in addition to decyclizing the cyclopropyl ring, the moiety herein referred to as Z is cleaved, yielding the first intermediate compound.
Alternatively, the above halogenation can comprise two separate steps. In the first step, the regioisomer of the present invention is decyclized under conditions effective to produce an oxobutyl derivative having the formula: 
Decyclizing can be effected with a halogen nucleophile and a Lewis Acid under conditions described above. At this point, the oxobutyl derivative can optionally be purified to remove excess decyclizing reagent. The oxobutyl derivative is converted to the first intermediate compound by treatment of the oxobutyl derivative with a mineral acid, such as hydrochloric acid, hydrobromic acid, or hydroiodic acid. It is preferred that treatment with acid be effected separately from the decyclizing. Further, it is preferred that treatment with acid be effected on purified oxobutyl derivative, rather than on oxobutyl derivative contaminated with excess decyclizing agent.
As indicated above, the regioisomer can also be converted to the oxobutyl derivative by hydroxylation, alkoxylation, or aryloxylation. In such cases, X3 is OR19, where R19 can be hydrogen, an alkyl group, or an aryl group. Alkoxylation or aryloxylation is carried out by reacting the regioisomcr with mineral acids in an solution of the appropriate alcohol, such as methanol when R19 is methyl, ethanol when R19 is ethyl, and phenol when R19 is phenyl. Hydroxylation can be effected by treating the regioisomer with mineral acids in an aqueous solution. The intermediate hydroxy compound can then be converted to a sulfonate ester, such as the tosylate or mesylate ester, by reaction with a sulfonyl halide, such as p-toluenesulfonyl chloride or methanesulfonyl chloride.
If desired, the acid group of the first intermediate compound can be esterified by techniques well known to those skilled in the art, such as by evaporating an alcoholic solution of the acid and a mineral acid, such as a methanolic, ethanolic, propanolic, or butanolic solution of hydrochloric, hydrobromic, or hydroiodic acid, to dryness to form an ester having the formula: 
After halogenation, alkoxylation, or aryloxylation and optional esterification, the first intermediate compound or ester thereof can be reacted with a piperidine compound of the formula: 
under conditions effective to form the piperidine derivative compound having a keto group of the formula: 
This alkylation reaction is carried out in a suitable solvent preferably in the presence of a base and, optionally, in the presence of a catalytic amount of potassiumi iodide for about 4 to 120 hours at a temperature of about 70xc2x0 C. to the reflux temperature of the solvent. Suitable solvents for the alkylation reaction include alcohol solvents, such as, methanol, ethanol, isopropyl alcohol, or n-butanol; ketone solvents, such as methyl isobutyl ketone and methyl ethyl ketone; hydrocarbon solvents, such as benzene, toluene, or xylene; halogenated hydrocarbons, such as, chlorobenrzene or methylene chloride; or dimethylformamide. Suitable bases for the alkylation reaction include inorganic bases, for example, sodium bicarbonate, potassium carbonate, or potassium bicarbonate or organic bases, such as a trialkylamine, for example, triethylamine or pyridine, or an excess of the piperidine compound can be used. When the piperidine derivative is in the form of an ester, it can be hydrolyzed to a carboxylic acid.
Piperidine derivative compounds of the present invention having n equal to 1 can also be prepared by the following alternative alkylation procedure. Subsequent to halogenation and optional esterification, the first intermediate compound having the formula: 
is reacted with 4-hydroxypiperidine in an organic solvent, such as toluene, dioxane, xylene, methyl ethyl ketone, methyl isobutyl ketone, or N,N-dimethylformamide, at a temperature between 80xc2x0 and 140xc2x0 C. and in the presence of an acid-binding agent, such as an alkali metal carbonate or bicarbonate, to form an N-substituted hydroxypiperidine having the formula: 
The N-substituted hydroxypiperidine is then reacted with a diphenylmonohalomethane having the formula: 
wherein X4 is a halogen, under conditions effective to forrn the piperidine derivative compound of the formula: 
The reaction is preferably carried out in an inert organic solvent, for example, toluene, xylene, dioxane, methyl isobut,l ketone, or N,N-dimethylformamide, at a temperature between 80xc2x0 and 140xc2x0 C. in the presence of an acid-binding agent such as an alkali metal carbonate or bicarbonate. The diphenylmonohalomethanes can be obtained commercially, or they can be prepared by the methods known in the art, for example, by reaction of the corresponding diphenylmethanol with a phosphorous or thionyl chloride or bromide in an inert organic solvent. This alternative alkylation method is preferred when R3 in the first intermediate compound is xe2x80x94COOH.
Irrespective of the alkylation procedure employed, when R3 is xe2x80x94COOalkyl, the alkylation reaction can be followed by base hydrolysis to convert R3 substituents that are xe2x80x94COOalkyl groups to xe2x80x94COOH groups. Such base hydrolysis involves treatment of the piperidine derivative with an inorganic base, such as sodium hydroxide, in an aqueous lower alcohol solvent, such as aqueous methanol, ethanol, isopropyl alcohol, or n-butanol, at reflux temperature for about xc2xd hour to 12 hours.
Piperidine compounds where n=0 and each of R1 and R2 is hydrogen or where n=0 and R1 is hydroxy and R2 is hydrogen are commercially available or may be prepared according to procedures well known in the art (e.g. F. J. McCarty, C. H. Tilford, M. G. Van Campen, J. Am. Chem. Soc., 1961, 26, 4084, which is hereby incorporated by reference). Piperidine compounds wherein n=0 and R1 and R2 form a second bond between the carbon atoms bearing R1 and R2 may be prepared by dehydration of the corresponding compound wherein R1 is hydroxy by procedures generally known in the art. Piperidine compounds wherein n=1 and R1 and R2 are both hydrogen are prepared by condensation of an appropriately substituted diphenylmonohalomethane, such as diphenylchloromethane, diphenylbromomethane, and di(p-tolyl)chloromethane, with a 1-alkoxycarbonyl-4-hydroxypiperidine in a suitable solvent, such as toluene, xylene, dioxane, methyl isobutylketone, or N,N-dimethylformamide. The reaction is conducted at a temperature between 80xc2x0 C. and 140xc2x0 C. and in the presence of a base, such as an alkali metal carbonate or bicarbonate. Following the reaction, hydrolysis with alkali metal hydroxide in an organic solvent, such as ethanol or isopropanol, at the boiling point of the solvent, yields the 4-(diarylmethoxy)-piperidine free base.
In yet another aspect of the present invention, the piperidine derivative compound is produced by decyclizing the regioisomer of the present invention under conditions effective to produce a oxobutyl derivative compound having the formula: 
Decyclization can be effccted by reacting the regioisomer with a halogen nucleophile and a Lewis Acid. Decyclization is carried out in a suitable solvent, optionally in the presence of a catalytic amount of an optional nucleophile, for about 0.5 to 24 hours and a temperature of about xe2x88x9240 degrees C to the reflux temperature of the solvent. Suitable halogen, Lewis Acids, and solvents include those which were discussed above in regard to halogenating the regioisomer.
The oxobutyl derivative compound is converted to a piperidine derivative precursor having the formula: 
by reacting the oxobutyl derivative with a piperidine compound having the formula: 
under conditions effective to form the piperidine derivative precursor. This alkylation reaction is carried out in a suitable solvent preferably in the presence of a base and, optionally, in the presence of a catalytic amount of potassium iodide for about 4 to 120 hours at a temperature of about 70xc2x0 C. to the reflux temperature of the solvent. Suitable solvents for the alkylation reaction include alcohol solvents, such as, methanol, ethanol, isopropyl alcohol, or n-butanol; ketone solvents, such as, methyl isobutyl ketone and methyl ethyl ketone; hydrocarbon solents, such as, benzene, toluene, or xylene; halogenated hydrocarbons, such as, chlorobenzene or methylene chloride; or dimethylformamnide. Suitable bases for the alkylation reaction include inorganic bases, for example, sodium bicarbonate, potassium carbonate, or potassium bicarbonate or organic bases, such as a trialkylamine, for example, triethylamine or pyridine, or an excess of the piperidine compound can be used.
Alternatively, piperidine derivative precursors of the present invention having n equal to 1 can also be prepared by reacting the oxobutyl derivative having the formula: 
with 4-hydroxypiperidine in an organic solvent, such as toluene, dioxane, xylene, methyl isobutyl ketone, or N,N-dimethylformamide, at a temperature between 80xc2x0 and 140xc2x0 C. and in the presence of an acid-binding agent, such as an alkali metal carbonate or bicarbonate, to form an N-substituted hydroxypiperidine having the formula: 
The N-substituted hydroxypiperidine is then reacted with a diphenylmonohalomethane having the formula: 
wherein X4 is a halogen, under conditions effective to form the piperidine derivative precursor of the formula: 
The reaction is preferably carried out in an inert organic solvent, for example, toluene, xylene, dioxane, methyl isobutyl ketone, or N,N-dimethylformamide, at a temperature between 80xc2x0 and 140xc2x0 C. in the presence of an acid-binding agent such as an alkali metal carbonate or bicarbonate.
Irrespective of the alkylation procedure employed, the piperidine derivative precursor is then converted to the piperidine derivative having the formula: 
This conversion can be effected by treatment of the piperidine derivative precursor with a mineral acid, such as hydrochloric acid, hydrobromic acid, or hydroiodic acid in a suitable organic solvent, for about 0.5 to 24 hours and a temperature of about xe2x88x9240 degrees C. to the reflux temperature of the solvent. Suitable solvents include alcohols, such as methanol, ethanol, isopropanol, and various glycols; hydrocarbon solvents, such as, benzene, toluene, xylene, or cyclohexane; ethereal solvents such as ether, tetrahydrofuran, dioxane, or dimethoxyethane; or halogenated hydrocarbons, such as, chlorobenzene, methylene chloride, carbon tetrachloride, chloroform, or dichloroethane. Alternatively, this conversion can be effected in vivo by administering the piperidine derivative percursor to a subject, and permitting the subject to metabolize the piperidine derivative precursor to the piperidine derivative compound.
Piperidine derivative precursors of the present invention can be used to treat patients suffering from allergic reactions, such as asthma, allergic rhinitis, and other conditions which can be treated with piperidine derivative compounds. Treatment includes administering to the patient an effective amount of the piperidine derivative precursor. The amounts and modes of administration are the same as those discussed above for administration of piperidine derivative compounds.
As discussed above, the process of the present invention is useful in producing piperidine derivatives with either a keto group or a hydroxyl group. Derivatives with keto groups can be converted to similar compounds with hydroxyl groups by reduction reactions which are well known in the art.
Reduction can be carried out with sodium borohydride or potassium borohydride in lower alcohol solvents, such as, methanol, ethanol, isopropyl alcohol, or n-butanol.
When lithium aluminum hybride or diborane are used as reducing agents, suitable solvents are ethers, for example, diethyl ether, tetrahydrofuran, or dioxane. These reduction reactions are carried out at temperatures ranging from about 0xc2x0 C. to the reflux temperature of the solvent, and the reaction time varies from about 0.5 to 8 hours.
Catalytic reduction with hydrogen may also be employed using, for example, Raney nickel, palladium, platinum, or rhodium catalysts in lower alcohol solvents, such as, methanol, ethanol, isopropyl alcohol, or n-butanol or acetic acid or their aqueous mixtures, or by the use of aluminum isopropoxide in isopropyl alcohol. Reduction using sodium borohydride is generally preferred over catalytic reduction when forming carboxylic acids or esters.
The piperidine derivative containing a hydroxy group thus prepared can optionally be separated into its enantiomerically pure components by conventional methods. For example, the racemic mixture of piperidine derivative enantiomers can be converted to a racemic mixture of diastereomers with a reactive chiral agent. The diastereomers are then separated by, for example, recrystallization or chromatography, and the pure enantiomer is recovered by cleaving the reactive chiral agent. Alternatively, the racemic mixture of piperidine derivative enantiomers can be chromatographically separated using chiral stationary phases or by recrystallization by usinq chiral solvents.
Piperidine derivatives having keto groups can also be converted to enantiomerically pure piperidine derivatives having hydroxy groups by using chiral reducing agents. For example, reduction using (+)-B-chlorodiisopropinocamphenylborane produces the piperidine derivative having R chirality at the carbon to which the hydroxy group is bonded. Alternatively, by using (xe2x88x92)-B-chlorodiisopropinocamphenylborane produces the S enantiomer. Other suitable chiral reducing agents are (R) and (S)-oxazaborolidine/BH3, potassium 9-O-(1,2:5,6-di-O-isopropylidine-xcex1-D-glucofuransoyl)-9-boratabicyclo [3.3.1]nonane, (R) and (S)-B-3-pinanyl-9-borabicyclo[3.3.1]nonane, NB-enantride, lithium (R)-(+) and (S)-(xe2x88x92)-2,2xe2x80x2-dihydroxy-1,1xe2x80x2-binaphthyl alkoxyl aluminum hydride, (R)-(+)-and (S)-(xe2x88x92)-2,2xe2x80x2-dihydroxy-6,6xe2x80x2-dimethylbiphenyl borane-amine complex, tris(((1S, 2S, 5R)-2-isoprophy-5-methyl-cyclohex-1-yl)methyl)aluminum, (((1R, 3R)-2,2-dimethylbicyclo[2.2.1]hept-3-yl)methyl)beryllium chloride, (R)-BINAP-ruthenium complex/H2, and 6,6xe2x80x2-bis(diphenylphosphino)-3,3xe2x80x2-dimethoxy-2,2xe2x80x2,4,4xe2x80x2-tetramethyl-1,1xe2x80x2-biphenyl.
When esters with hydroxyl groups have been formed, base hydrolysis can be used to produce a carboxylic acid. Such procedures are well known and generally involve treatment with an inorganic base, such as, sodium hydroxide or potassium hydroxide, in an aqueous lower alcoholic solvent, such as aqueous methanol, ethanol, isopropyl alcohol, or n-butanol. Base hydrolysis is carried out at a temperature from about room temberature to about the solvent reflux temperature for about xc2xd hour to 12 hours.
In like manner, piperidine derivative precursors bearing a keto group and having the formula: 
can be reduced to piperidine derivative precursors bearing a hydroxyl group having the formula: 
The piperidine derivative precursors bearing a hydroxyl group can be converted to the piperidine derivative having the formula: 
in vitro, such as by treating the piperidine derivative precursor bearing a hydroxyl group with strong acid, as discussed above, or, alternatively, in vivo, by administering the piperidine derivative precursor bearing a hydroxyl group to a subject. Piperidine derivative precursors bearing hydroxyl cyroups, like piperidine derivative precursors bearing keto groups, can be used to treat allergic reactions, such as asthma or allergic rhinitis.